Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. We have discovered that d T cells constitute an unexpected but substantial reservoir of persistent, latent infection. We recovered latent but replication-competent HIV from highly purified T cells of the Vd2 class from 14 of 18 aviremic patients on long-standing antiretroviral therapy. In nine of these 14 patients, HIV was recovered when as few as 15,000 cells were cultured, reflecting a high frequency of infection. We found that primary isolated peripheral blood Vd2 cells can be infected in vitro through activation-induced upregulation of the CD4 receptor and propose that HIV-induced immune activation may allow infection of d T cells in vivo. We propose to extend our studies of latent infection in Vd2 T cells, survey Vd1 T cells to determine if they are latently infected as well, and then perform longitudinal studies to verify the persistence and more accurately quantitate infection in this new reservoir. We will then explore whether latency in these cells can be disrupted by the same therapeutic approaches that our group is developing to target latency within central memory CD4+ T cells, or if novel, d-specific approaches to this reservoir are needed. Finally, given the predominance of d T cells within the tissue we will directly study infection and latency of these cells in GALT and lymph node tissue. Our investigations will contribute critically to the effort to define and attack HIV infection within persistent, latently infected cells.